Abstract
Hedgehog (Hh) signaling plays a broad role in the development of many organs including bone and teeth. It is noted that sustained Hh activity in osteoblasts negatively regulates postnatal development in mice. However, it remains unknown whether Hh signaling contributes to cementum formation. In this study, to define the roles of Hh signaling in cementum formation, we analyzed two kinds of transgenic mouse models for Hh signaling activation designed by the inactivation of Suppressor of Fused (Sufu), a negative regulator of Hh signaling, (SufuOC) and a forced endogenous activation of Smo (SmoM2OC) under the control of osteocalcin (OC) promoter-driven Cre recombinase. Interestingly, cellular cementum apposition was remarkably reduced in both mutants. Consistently, matrix formation and mineralization ability were down-regulated in OCCM-30, a cementoblast cell line, following treatment with a pharmaceutical Smo agonist. In addition, reductions in Osx expression and β-catenin activity, which are critical for cellular cementum formation, were also detected in vitro. Furthermore, the compound mutant mice designed for the stabilization of β-catenin with both Hh-Smo signaling activation in cementoblasts revealed a complete restoration of defective cellular cementum. In addition, Wnt antagonists such as Sostdc1 and Dkk1 were also induced by Smo activation and played a role in the reduction of Osx expression and β-catenin activity. Collectively, our data demonstrated that Hh signaling negatively regulates cementum apposition in a Wnt/β-catenin/Osx-dependent manner.
Highlights
Hedgehog (Hh) signaling plays a broad role in the development of many organs including bone and teeth
To study the gene regulatory networks downstream of the Hh-Smo signaling cascade in cementum formation during tooth development, we generated two kinds of mice for Hh-Smo activation, which are conditionally inactive for Suppressor of Fused (Sufu) (SufuOC) and constitutively active for Smo (SmoM2OC) in OC-positive dental mesenchyme
More dramatic changes in the gross cellular cementum mass of the mandibular first molar were observed in SmoM2OC than in SufuOC mice and the gap in the amount of cementum mass between the two mutants increased with aging as analyzed by the cementum area up to P56 (Fig. 1b and Supplementary Fig. S2b)
Summary
Hedgehog (Hh) signaling plays a broad role in the development of many organs including bone and teeth. It is noted that sustained Hh activity in osteoblasts negatively regulates postnatal development in mice It remains unknown whether Hh signaling contributes to cementum formation. Reductions in Osx expression and β-catenin activity, which are critical for cellular cementum formation, were detected in vitro. The compound mutant mice designed for the stabilization of β-catenin with both Hh-Smo signaling activation in cementoblasts revealed a complete restoration of defective cellular cementum. Hh signaling targets Ptc[1] and Gli[1] in vertebrates, and the presence of Ptc[1] and Gli[1] transcripts indicates the functional activation of Hh signaling[11,12] It is well-known that Suppressor of Fused (Sufu) negatively regulates Hh signaling by direct binding to the Gli protein[13]. We investigated the role of Hh-Smo signaling in cementum formation using multiple approaches and demonstrated that the activation of Hh-Smo signaling in cementoblasts leads to defective cementum formation through the inactivation of Osx and β-catenin
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